Polymerization mechanism of the Candida albicans virulence factor candidalysin.

Candida albicans is a commensal fungus that can cause epithelial infections and life-threatening invasive candidiasis. The fungus secretes candidalysin (CL), a peptide that causes cell damage and immune activation by permeation of epithelial membranes. The mechanism of CL action involves strong peptide assembly into polymers in solution. The free ends of linear CL polymers can join, forming loops that become pores upon binding to membranes. CL polymers constitute a therapeutic target for candidiasis, but little is known about CL self-assembly in solution. Here, we examine the assembly mechanism of CL in the absence of membranes using complementary biophysical tools, including a new fluorescence polymerization assay, mass photometry, and atomic force microscopy. We observed that CL assembly is slow, as tracked with the fluorescent marker C-laurdan. Single-molecule methods showed that CL polymerization involves a convolution of four processes. Self-assembly begins with the formation of a basic subunit, thought to be a CL octamer that is the polymer seed. Polymerization proceeds via the addition of octamers, and as polymers grow they can curve and form loops. Alternatively, secondary polymerization can occur and cause branching. Interplay between the different rates determines the distribution of CL particle types, indicating a kinetic control mechanism. This work elucidates key physical attributes underlying CL self-assembly which may eventually evoke pharmaceutical development.

Candidalysin: Connecting the pore forming mechanism of this virulence factor to its immunostimulatory properties.

Candida albicans is a deadly pathogen responsible for millions of mucosal and systemic infections per year. The pathobiology of C. albicans is largely dependent on the damaging and immunostimulatory properties of the peptide candidalysin (CL), a key virulence factor. When CL forms pores in the plasma membrane of epithelial cells, it activates a response network grounded in activation of the epidermal growth factor receptor. Prior reviews have characterized the resulting CL immune activation schemas but lacked insights into the molecular mechanism of CL membrane damage. We recently demonstrated that CL functions by undergoing a unique self-assembly process; CL forms polymers and loops in aqueous solution prior to inserting and forming pores in cell membranes. This mechanism, the first of its kind to be observed, informs new therapeutic avenues to treat Candida infections. Recently, variants of CL were identified in other Candida species, providing an opportunity to identify the residues that are key for CL to function. In this review, we connect the ability of CL to damage cell membranes to its immunostimulatory properties.

Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) commonly targeted for inhibition by anticancer therapeutics. Current therapeutics target EGFR's kinase domain or extracellular region. However, these types of inhibitors are not specific for tumors over healthy tissue and therefore cause undesirable side effects. Our lab has recently developed a new strategy to regulate RTK activity by designing a peptide that specifically binds to the transmembrane (TM) region of the RTK to allosterically modify kinase activity. These peptides are acidity-responsive, allowing them to preferentially target acidic environments like tumors. We have applied this strategy to EGFR and created the PET1 peptide. We observed that PET1 behaves as a pH-responsive peptide that modulates the configuration of the EGFR TM through a direct interaction. Our data indicated that PET1 inhibits EGFR-mediated cell migration. Finally, we investigated the mechanism of inhibition through molecular dynamics simulations, which showed that PET1 sits between the two EGFR TM helices; this molecular mechanism was additionally supported by AlphaFold-Multimer predictions. We propose that the PET1-induced disruption of native TM interactions disturbs the conformation of the kinase domain in such a way that it inhibits EGFR's ability to send migratory cell signals. This study is a proof-of-concept that acidity-responsive membrane peptide ligands can be generally applied to RTKs. In addition, PET1 constitutes a viable approach to therapeutically target the TM of EGFR.

The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease.

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC), caused primarily by the human fungal pathogen Candida albicans, results in significant quality-of-life issues for women worldwide. Candidalysin, a toxin derived from a polypeptide (Ece1p) encoded by the ECE1 gene, plays a crucial role in driving immunopathology at the vaginal mucosa. This study aimed to determine if expression and/or processing of Ece1p differs across C. albicans isolates and whether this partly underlies differential pathogenicity observed clinically. Using a targeted sequencing approach, we determined that isolate 529L harbors a similarly expressed, yet distinct Ece1p isoform variant that encodes for a predicted functional candidalysin; this isoform was conserved amongst a collection of clinical isolates. Expression of the ECE1 open reading frame (ORF) from 529L in an SC5314-derived ece1Δ/Δ strain resulted in significantly reduced vaginopathogenicity as compared to an isogenic control expressing a wild-type (WT) ECE1 allele. However, in vitro challenge of vaginal epithelial cells with synthetic candidalysin demonstrated similar toxigenic activity amongst SC5314 and 529L isoforms. Creation of an isogenic panel of chimeric strains harboring swapped Ece1p peptides or HiBiT tags revealed reduced secretion with the ORF from 529L that was associated with reduced virulence. A genetic survey of 78 clinical isolates demonstrated a conserved pattern between Ece1p P2 and P3 sequences, suggesting that substrate specificity around Kex2p-mediated KR cleavage sites involved in protein processing may contribute to differential pathogenicity amongst clinical isolates. Therefore, we present a new mechanism for attenuation of C. albicans virulence at the ECE1 locus.

Heterosynaptic plasticity in biomembrane memristors controlled by pH.

Abstract: In biology, heterosynaptic plasticity maintains homeostasis in synaptic inputs during associative learning and memory, and initiates long-term changes in synaptic strengths that nonspecifically modulate different synapse types. In bioinspired neuromorphic circuits, heterosynaptic plasticity may be used to extend the functionality of two-terminal, biomimetic memristors. In this article, we explore how changes in the pH of droplet interface bilayer aqueous solutions modulate the memristive responses of a lipid bilayer membrane in the pH range 4.97-7.40. Surprisingly, we did not find conclusive evidence for pH-dependent shifts in the voltage thresholds (V*) needed for alamethicin ion channel formation in the membrane. However, we did observe a clear modulation in the dynamics of pore formation with pH in time-dependent, pulsed voltage experiments. Moreover, at the same voltage, lowering the pH resulted in higher steady-state currents because of increased numbers of conductive peptide ion channels in the membrane. This was due to increased partitioning of alamethicin monomers into the membrane at pH 4.97, which is below the pKa (~5.3-5.7) of carboxylate groups on the glutamate residues of the peptide, making the monomers more hydrophobic. Neutralization of the negative charges on these residues, under acidic conditions, increased the concentration of peptide monomers in the membrane, shifting the equilibrium concentrations of peptide aggregate assemblies in the membrane to favor greater numbers of larger, increasingly more conductive pores. It also increased the relaxation time constants for pore formation and decay, and enhanced short-term facilitation and depression of the switching characteristics of the device. Modulating these thresholds globally and independently of alamethicin concentration and applied voltage will enable the assembly of neuromorphic computational circuitry with enhanced functionality. Impact statement: We describe how to use pH as a modulatory "interneuron" that changes the voltage-dependent memristance of alamethicin ion channels in lipid bilayers by changing the structure and dynamical properties of the bilayer. Having the ability to independently control the threshold levels for pore conduction from voltage or ion channel concentration enables additional levels of programmability in a neuromorphic system. In this article, we note that barriers to conduction from membrane-bound ion channels can be lowered by reducing solution pH, resulting in higher currents, and enhanced short-term learning behavior in the form of paired-pulse facilitation. Tuning threshold values with environmental variables, such as pH, provide additional training and learning algorithms that can be used to elicit complex functionality within spiking neural networks. Supplementary information: The online version contains supplementary material available at 10.1557/s43577-022-00344-z.

Prevalence of non-alcoholic fatty liver disease and its association with lifestyle habits in adults in Chile: a cross-sectional study from the National Health Survey 2016-2017.

Non-alcoholic fatty liver disease (NAFLD) represents an excessive fat accumulation within the liver, usually associated with excess body weight. A liver biopsy is the gold standard for diagnosis, but it is inapplicable in population-based studies. In large populations, non-invasive methods could be used, which may also serve to identify potential protective factors. We aimed to (a) estimate NAFLD prevalence in the adult population in Chile by using non-invasive methods and (b) determine the association between the presence of NAFLD and lifestyle habits. The National Health Survey of Chile 2016­2017 was analysed. We included individuals aged 21­75 years, without infectious diseases nor risky alcohol consumption. NAFLD was detected by either fatty liver index (FLI; considers circulating TAG, circulating γ-glutamyl-transferase, BMI and waist circumference), lipid accumulation product (LAP; considers sex, circulating TAG and waist circumference) or their combination. Lifestyle habits were determined by questionnaires. We included 2774 participants, representative of 10 599 094 (9 831 644, 11 366 544) adults in Chile. NAFLD prevalence (95 % CI) was 39·4 % (36·2, 42·8) by FLI, 27·2 % (24·2, 30·4) by LAP and 23·5 % (20·7, 26·5) by their combination. The prevalence progressively increased with increasing BMI. Of note, less smoking and more moderate-vigorous physical activity and whole-grain consumption were associated with lower odds of having NAFLD, independently of BMI. At least one out of four adults in Chile is afflicted with NAFLD. Health promotion strategies focused on controlling excess body weight and promoting specific lifestyle habits are urgently required.

The burden of liver disease in Latin America.

Liver disease poses a substantial burden in Latin America. This burden is primarily attributed to a high level of alcohol consumption and the increasing prevalence of risk factors associated with metabolic dysfunction-associated steatotic liver disease (MASLD), such as sedentary lifestyles, easy access to ultra-processed foods, obesity, and type 2 diabetes mellitus. These epidemiological trends are cause for concern, especially considering that there are significant challenges in addressing them, due to disparities in access to liver disease screening and care. In this article, we aim to provide an overview of the current situation regarding liver disease in Latin America. We also discuss recent multinational proposals designed to address the growing MASLD burden via its integration into existing non-communicable diseases policies, at both local and global levels. Additionally, we emphasize the urgent need to establish effective public health policies that target both MASLD risk factors and excessive alcohol consumption. Furthermore, we discuss the development of liver transplantation programs, areas for improvement in medical education and research capabilities, and how the fostering of extensive collaboration among all stakeholders is crucial for addressing liver disease in the region.

How cholesterol stiffens unsaturated lipid membranes.

Cholesterol is an integral component of eukaryotic cell membranes and a key molecule in controlling membrane fluidity, organization, and other physicochemical parameters. It also plays a regulatory function in antibiotic drug resistance and the immune response of cells against viruses, by stabilizing the membrane against structural damage. While it is well understood that, structurally, cholesterol exhibits a densification effect on fluid lipid membranes, its effects on membrane bending rigidity are assumed to be nonuniversal; i.e., cholesterol stiffens saturated lipid membranes, but has no stiffening effect on membranes populated by unsaturated lipids, such as 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). This observation presents a clear challenge to structure-property relationships and to our understanding of cholesterol-mediated biological functions. Here, using a comprehensive approach-combining neutron spin-echo (NSE) spectroscopy, solid-state deuterium NMR (2H NMR) spectroscopy, and molecular dynamics (MD) simulations-we report that cholesterol locally increases the bending rigidity of DOPC membranes, similar to saturated membranes, by increasing the bilayer's packing density. All three techniques, inherently sensitive to mesoscale bending fluctuations, show up to a threefold increase in effective bending rigidity with increasing cholesterol content approaching a mole fraction of 50%. Our observations are in good agreement with the known effects of cholesterol on the area-compressibility modulus and membrane structure, reaffirming membrane structure-property relationships. The current findings point to a scale-dependent manifestation of membrane properties, highlighting the need to reassess cholesterol's role in controlling membrane bending rigidity over mesoscopic length and time scales of important biological functions, such as viral budding and lipid-protein interactions.

PIP2 promotes conformation-specific dimerization of the EphA2 membrane region.

The impact of the EphA2 receptor on cancer malignancy hinges on the two different ways it can be activated. EphA2 induces antioncogenic signaling after ligand binding, but ligand-independent activation of EphA2 is pro-oncogenic. It is believed that the transmembrane (TM) domain of EphA2 adopts two alternate conformations in the ligand-dependent and the ligand-independent states. However, it is poorly understood how the difference in TM helical crossing angles found in the two conformations impacts the activity and regulation of EphA2. We devised a method that uses hydrophobic matching to stabilize two conformations of a peptide comprising the EphA2 TM domain and a portion of the intracellular juxtamembrane (JM) segment. The two conformations exhibit different TM crossing angles, resembling the ligand-dependent and ligand-independent states. We developed a single-molecule technique using styrene maleic acid lipid particles to measure dimerization in membranes. We observed that the signaling lipid PIP2 promotes TM dimerization, but only in the small crossing angle state, which we propose corresponds to the ligand-independent conformation. In this state the two TMs are almost parallel, and the positively charged JM segments are expected to be close to each other, causing electrostatic repulsion. The mechanism PIP2 uses to promote dimerization might involve alleviating this repulsion due to its high density of negative charges. Our data reveal a conformational coupling between the TM and JM regions and suggest that PIP2 might directly exert a regulatory effect on EphA2 activation in cells that is specific to the ligand-independent conformation of the receptor.

ATP-Responsive Liposomes via Screening of Lipid Switches Designed to Undergo Conformational Changes upon Binding Phosphorylated Metabolites.

Liposomal delivery vehicles can dramatically enhance drug transport. However, their clinical application requires enhanced control over content release at diseased sites. For this reason, triggered release strategies have been explored, although a limited toolbox of stimuli has thus far been developed. Here, we report a novel strategy for stimuli-responsive liposomes that release encapsulated contents in the presence of phosphorylated small molecules. Our formulation efforts culminated in selective cargo release driven by ATP, a universal energy source that is upregulated in diseases such as cancer. Specifically, we developed lipid switches 1a-b bearing two ZnDPA units designed to undergo substantial conformational changes upon ATP binding, thereby disrupting membrane packing and triggering the release of encapsulated contents. Dye leakage assays using the hydrophobic dye Nile red validated that ATP-driven release was selective over 11 similar phosphorylated metabolites, and release of the hydrophilic dye calcein was also achieved. Multiple alternative lipid switch structures were synthesized and studied (1c-d and 2), which provided insights into the structural features that render 1a-b selective toward ATP-driven release. Importantly, analysis of cellular delivery using fluorescence microscopy in conjunction with pharmacological ATP manipulation showed that liposome delivery was specific, as it increased upon intracellular ATP accumulation, and was inhibited by ATP downregulation. Our new approach shows strong prospects for enhancing the selectivity of release and payload delivery to diseased cells driven by metabolites such as ATP, providing an exciting new paradigm for controlled release.

Synthesis and Characterization of Core-Shell Cu-Ru, Cu-Rh, and Cu-Ir Nanoparticles.

Optimizing the use of expensive precious metals is critical to developing sustainable and low-cost processes for heterogeneous catalysis or electrochemistry. Here, we report a synthesis method that yields core-shell Cu-Ru, Cu-Rh, and Cu-Ir nanoparticles with the platinum-group metals segregated on the surface. The synthesis of Cu-Ru, Cu-Rh, and Cu-Ir particles allows maximization of the surface area of these metals and improves catalytic performance. Furthermore, the Cu core can be selectively etched to obtain nanoshells of the platinum-group metal components, leading to a further increase in the active surface area. Characterization of the samples was performed with X-ray absorption spectroscopy, X-ray powder diffraction, and ex situ and in situ transmission electron microscopy. CO oxidation was used as a reference reaction: the three core-shell particles and derivatives exhibited promising catalyst performance and stability after redox cycling. These results suggest that this synthesis approach may optimize the use of platinum-group metals in catalytic applications.

Post-transplant mortality and graft failure after induction immunosuppression among Black heart transplant recipients in the United States.

Black heart transplant recipients are more likely to receive induction immunosuppression compared to other races because of higher rates of acute rejection, graft failure, and mortality. However, it is not known whether contemporary induction immunosuppression improves their post-transplant outcomes. To evaluate whether Black patients who were prescribed induction immunosuppression therapy have lower all-cause mortality or graft-failure rates compared to those who were not, we studied Black U.S. adult heart transplant recipients in the Scientific Registry of Transplant Recipients database (2008-2018). We used multivariable Cox proportional hazards regression analysis to compare the hazards of all-cause mortality or graft failure as a composite, for patients who were prescribed induction immunosuppression and those who were not. Among 5160 recipients, 2787 (54.0%) were prescribed induction immunosuppression and 2373 (46.0%) were not. There was no evidence of survival differences according to induction immunosuppression for the composite of all-cause mortality or graft failure (aHR = 1.13, 95% CI 0.96-1.32), mortality (aHR = 1.14, 95% CI 0.97-1.34), graft failure (aHR = 1.05, 95% CI 0.82-1.34) and acute rejection (aHR = 1.00, 95% CI 0.89-1.12). Given the side effects of treatment, future guidelines should reconsider the recommendation for induction immunosuppression among Black patients.

The L-α-Lysophosphatidylinositol/G Protein-Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis.

BACKGROUND AND AIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing ß-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.

On 'Fourier transform infrared study of proteins with parallel ß-chains' by Heino Susi, D. Michael Byler.

In 1987, Susi & Byler published a groundbreaking paper for the determination of the secondary structure of proteins. Notably, they determined the characteristic signature of the ß-strand in the infrared spectrum. As a result, Fourier-transform infrared spectroscopy became a general method to determine protein structure.

Clinical impact of immunotherapy in Merkel cell carcinoma patients: A systematic review and meta-analysis.

BACKGROUND: Immunotherapy is emerging as an alternative treatment for Merkel cell carcinoma, but its long-term effects on response, survival, and safety are not well established. High-quality evidence is needed to estimate the efficacy of this treatment and to review the characteristics of patients and tumors that might improve outcomes. OBJECTIVE: To summarize efficacy and safety of immunotherapy in patients with Merkel cell carcinoma. METHODS: A systematic review was performed for studies published in MEDLINE, Web of Science, Scopus, and EMBASE. Two reviewers examined the literature and data extraction in duplicate. We estimated the proportions for objective responses, progression-free survival, overall survival, and treatment-related adverse events. Associations between objective response rate and immunobiologic markers were analyzed. RESULTS: Six clinical trials of 201 patients treated with immunotherapy were included. The objective response rate was 51% (95% confidence interval, 0.40-0.62; I2 = 37.1%) and grade ≥3 treatment-related adverse events were observed in 18% (95% confidence interval, 0.11-0.29; I2 = 49.5%) of patients. No significant difference was observed between response rates and immunobiologic characteristics. CONCLUSIONS: A significantly reduced tumor diameter with durable response rates and a safe profile are obtained with immunotherapy. Similar response rates achieved on either subgroup of viral status or programmed death ligand 1 expression suggests that it might act on multiple, unexplored pathways.

LDL particle size and antioxidant HDL function improve after sustained virological response in patients with chronic HCV.

HCV infection is associated with an increased incidence of cardiovascular (CV) events. Mechanisms underlying this association remain unknown. In our study, twenty HCV patients (median age 60.5 years, 65% male and 80% with cirrhosis) were evaluated prior, during and after direct-acting antiviral treatment. Ninety percent of patients achieved sustained virological response (SVR). Significant changes were observed in LDL particle size index, measured by LDL-C/apoB ratio, which increased after treatment (p = 0.023). In addition, HDL antioxidant capacity improved gradually from 34.4% at baseline to 42.4% at 4 weeks (p = 0.011), 65.9% at end of treatment EOT (p = 0.002) and remained elevated at 12-week (p = 0.001) after EOT compared to baseline values. Our findings suggest that a shift to a less atherogenic lipid profile may be a possible mechanism associated with CV risk reduction in patients with HCV infection achieving SVR.

Scoping review of COVID-19-related systematic reviews and meta-analyses: can we really have confidence in their results?

AIM: The aim of this study was to systematically appraise the quality of a sample of COVID-19-related systematic reviews (SRs) and discuss internal validity threats affecting the COVID-19 body of evidence. DESIGN: We conducted a scoping review of the literature. SRs with or without meta-analysis (MA) that evaluated clinical data, outcomes or treatments for patients with COVID-19 were included. MAIN OUTCOME MEASURES: We extracted quality characteristics guided by A Measurement Tool to Assess Systematic Reviews-2 to calculate a qualitative score. Complementary evaluation of the most prominent published limitations affecting the COVID-19 body of evidence was performed. RESULTS: A total of 63 SRs were included. The majority were judged as a critically low methodological quality. Most of the studies were not guided by a pre-established protocol (39, 62%). More than half (39, 62%) failed to address risk of bias when interpreting their results. A comprehensive literature search strategy was reported in most SRs (54, 86%). Appropriate use of statistical methods was evident in nearly all SRs with MAs (39, 95%). Only 16 (33%) studies recognised heterogeneity in the definition of severe COVID-19 as a limitation of the study, and 15 (24%) recognised repeated patient populations as a limitation. CONCLUSION: The methodological and reporting quality of current COVID-19 SR is far from optimal. In addition, most of the current SRs fail to address relevant threats to their internal validity, including repeated patients and heterogeneity in the definition of severe COVID-19. Adherence to proper study design and peer-review practices must remain to mitigate current limitations.

Effectiveness of Recruitment Strategies of Latino Smokers: Secondary Analysis of a Mobile Health Smoking Cessation Randomized Clinical Trial.

BACKGROUND: Latinos remain disproportionately underrepresented in clinical trials, comprising only 2%-3% of research participants. In order to address health disparities, it is critically important to increase enrollment of Latino smokers in smoking cessation trials. There is limited research examining effective recruitment strategies for this population. OBJECTIVE: The purpose of this study was to compare the effectiveness of direct versus mass and high- versus low-effort recruitment strategies on recruitment and retention of Latino smokers to a randomized smoking cessation trial. We also examine how the type of recruitment might have influenced the characteristics of enrolled participants. METHODS: Latino smokers were enrolled into Decídetexto from 4 states-New Jersey, Kansas, Missouri, and New York. Participants were recruited from August 2018 until March 2021. Mass recruitment strategies included English and Spanish advertisements to the Latino community via flyers, Facebook ads, newspapers, television, radio, church bulletins, and our Decídetexto website. Direct, high-effort strategies included referrals from clinics or community-based organizations with whom we partnered, in-person community outreach, and patient registry calls. Direct, low-effort strategies included texting or emailing pre-existing lists of patients who smoked. A team of trained bilingual (English and Spanish) recruiters from 9 different Spanish-speaking countries of origin conducted recruitment, assessed eligibility, and enrolled participants into the trial. RESULTS: Of 1112 individuals who were screened, 895 (80.5%) met eligibility criteria, and 457 (457/895, 51.1%) enrolled in the trial. Within the pool of screened individuals, those recruited by low-effort recruitment strategies (both mass and direct) were significantly more likely to be eligible (odds ratio [OR] 1.67, 95% CI 1.01-2.76 and OR 1.70, 95% CI 0.98-2.96, respectively) and enrolled in the trial (OR 2.60, 95% CI 1.81-3.73 and OR 3.02, 95% CI 2.03-4.51, respectively) compared with those enrolled by direct, high-effort strategies. Among participants enrolled, the retention rates at 3 months and 6 months among participants recruited via low-effort strategies (both mass and direct) were similar to participants recruited via direct, high-effort methods. Compared with enrolled participants recruited via direct (high- and low-effort) strategies, participants recruited via mass strategies were less likely to have health insurance (44.0% vs 71.2% and 71.7%, respectively; P<.001), lived fewer years in the United States (22.4 years vs 32.4 years and 30.3 years, respectively; P<.001), more likely to be 1st generation (92.7% vs 76.5% and 77.5%, respectively; P=.007), more likely to primarily speak Spanish (89.3% vs 65.8% and 66.3%, respectively), and more likely to be at high risk for alcohol abuse (5.8 mean score vs 3.8 mean score and 3.9 mean score, respectively; P<.001). CONCLUSIONS: Although most participants were recruited via direct, high-effort strategies, direct low-effort recruitment strategies yielded a screening pool more likely to be eligible for the trial. Mass recruitment strategies were associated with fewer acculturated enrollees with lower access to health services-groups who might benefit a great deal from the intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03586596; https://clinicaltrials.gov/ct2/show/NCT03586596. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-DOI: 10.1016/j.cct.2020.106188.

Fixed-bearing unicompartmental knee arthroplasty provides a lower failure rate than mobile-bearing unicompartimental knee arthroplasty when used after a failed high tibial osteotomy: a systematic review and meta-analysis.

Despite the fact that the choice of bearing design has been thought to influence the functional outcomes and longevity of unicompartimental knee arthroplasty (UKA), there is a lack of clinical evidence supporting the decision-making process in patients who have undergone high tibial osteotomy (HTO). A systematic review of studies was carried out that reported the outcomes of fixed-bearing (FB) or mobile-bearing (MB) medial UKA in patients with a previous HTO. A random effect meta-analysis using a generalized linear mixed-effects model to calculate revision rates was done. Seven retrospective cohort studies were included for this study. Regarding the fixation method, 40 were the FB-UKA and 47 were MB-UKA. For both groups, the mean post-operative follow-up was 5.8 years. The survival rates were 92% for the FB-UKA with a mean follow-up of 10 years. For the MB-UKA, it ranged from 35.7 to 93%, with a mean follow-up of 4.2 years. For the FB, the time to revision was reported as 9.3 years, while 1.2, 2.5 and 2.91 years was reported for the MB. The results of the meta-analysis showed that the revision rate for the patients receiving a FB-UKA after failed HTO was 8%, compared to 17% in those who received an MB-UKA. The results of the review suggest that the use of the FB-UKA is associated with lower revision rates and a longer survival time than the MB-UKA and have similar functional ability scores.Level of evidence: III (systematic review of level-III studies).